Etiologic Treatment of Chagas Disease: Old Drugs, New Insights, Challenges, and Perspectives

Abstract

We review the current status of etiological treatment for Chagas disease, focusing on the first ever randomized and placebo-controlled trials for the prevalent symptomatic and asymptomatic chronic stage of this condition, completed in the last 10 years using the clinically available drugs (the nitroheterocyclic derivatives benznidazole and nifurtimox, introduced empirically half a century ago), as well as novel candidates (the ergosterol biosynthesis inhibitors (SBI) posaconazole and fosravuconazole, a prodrug of ravuconazole). Three clinical trials investigated the parasitological efficacy of posaconazole (CHAGASAZOL, STOP CHAGAS) and fosravuconazole (E1224) in chronic patients without cardiac involvement and found that, at the doses used for the management of invasive fungal infections, these compounds were significantly less effective than benznidazole at the conventional dose (2.5 mg/kg bid for 60 days) to induce sustained parasitemia suppression 1 year after treatment initiation. A critical assessment of the objectives, design, and results of these studies leads to the proposal of novel therapeutic schemes with the established drugs and new entrants, including combination therapies, consistent with their mechanisms of actions and basic pharmacokinetic/pharmacodynamic analyses. In addition, two clinical trials investigated the effect of benznidazole administered at the conventional dose, which is highly effective against acute T. cruzi infections, on the clinical evolution of patients with (BENEFIT) and mostly without (TRAENA) cardiac compromise and found that, despite some evidence on reduction of the parasite load, no effect on the clinical deterioration of the patients was observed in a mean of 5-7 years follow-up after the end of treatment. Unfortunately, there were limitations on sample size and no assessment of durability of parasitological response for the evaluation of treatment in patients with no or early cardiac involvement. Finally, we also emphasize the critical need of biomarkers to evaluate early response to etiological treatment in chronic patients, and the potential need for combination of etiological treatment with host-directed therapies, including promoters of inflammation resolution and immunotherapy.